The reported synthesis of Omeprazole basically involves the coupling of intermediates A and B to form intermediate C which is oxidized to the sulfinyl or sulfoxy compound, Omeprazole. ##STR2## (See for example Canadian Letters Patent No. 1,127,158 Hassle)
Hassle used the N-oxide form of intermediate A: ##STR3## (See Canadian Letters Patent No. 1,234,118)
The N-Oxide form may be considered necessary to prepare the precursor 4-nitro compound and it is essential for the alkylation/functionalization of the 2-position (X), according to Hassle's process. Intermediate A (N-Deoxygenated) is then coupled with intermediate B on the route to Omeprazole.
Esteve, on the other hand, described a synthesis that involves coupling the N-oxides of the 4-nitro or the 4-Chloro with intermediate B to form the N-Oxide of intermediate C. Following that, Esteve either substituted at the pyridinyl 4-position with the methoxy and then reduced the N-Oxide or vice-versa. ##STR4## (See European Patent No. 484,265)
Torcan, reported a method that offers advantages involving the oxidation and the purification of the final product. Their method comprises oxidizing the amide of Intermediate C to the corresponding amide sulfinyl compound followed by hydrolysis and decarboxylation to form Omeprazole. Torcan did not report processes for the manufacture of the pyridinyl moiety. ##STR5## (See U.S. Pat. No. 5,374,730)
Other Oxidation methods used for converting the thioether "Intermediate C" to the sulfinyl are purportedly taught by recent Takeda (CA 1,263,119) and Hassle's (U.S. Pat. No. 5,386,032) patents.
C. L. Pharma's U.S. Pat. No. 5,066,810 teaches a process to manufacture ##STR6## where X is OH or Cl by catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine as depicted below ##STR7## in the presence of an inert diluent, the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine as depicted below ##STR8## which is then reacted with sodium nitrite in aqueous-acidic solution to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and ultimately reacting the latter with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine.
In European Patent Publication No. 0103553 and in Canadian Letters Patent 1,234,118 and in U.S. Pat. Nos. 4,544,750 and 4,620,008, the following synthetic route for the pyridine part of omeprazole is described: ##STR9##
More recently, a method for the synthesis of intermediate A was published by a Taiwanese group. This procedure consisted of preparation of a the pyrone, pyridone and pyridine derivatives that can be converted to intermediate A. (Heterocycles, 45,1997, 77).
There are certain disadvantages associated with the current manufacturing processes, largely derived from the N-Oxide intermediates. Nitropyridines and their N-oxides are suspected carcinogens and therefore are unsafe to handle. Also, the above processes employ the nitropyridines and their N-oxides in the early or late stages of the manufacture. In both cases the suspected carcinogens are potential impurities.
While the Taiwanese method does not employ nitropyridines or N-oxides, it suffers from the disadvantage that it employs a large number of steps (approximately 10 steps) and the low availability of the starting material. Both are factors that affect the manufacturing yield and cost.
It is therefore an object of the invention to provide a method of manufacturing intermediates useful in preparing medicines where said intermediates avoid N-oxides that are suspected carcinogens.
It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines where said method employs intermediates that are safe to handle.
It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines wherein the number of steps are minimal in number.
It is also another object of the invention to provide methods of manufacture which incorporate materials that are readily available.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention.